1. Field of the Invention
The present disclosure relates to pharmaceutical compositions and methods for reducing scar formation in a subject. More particularly, the disclosed invention relates to the use of a mixture of three nucleic acids for reducing scar formation.
2. Description of Related Art
Skin is the largest organ in human. It protects the internal organs/tissues from the environment. Vast numbers of people experience skin damages caused by trauma, burn or other external physical causes, as well as by diseases such as pressure, venous stasis and diabetes mellitus. The primary goals of the treatment of wounds include rapid wound closure and regeneration of functionally- and aesthetically-satisfactory skin tissues. However, wound healing is a dynamic, interactive process involving various factors, and despite the advances in cellular and molecular biology, the incidence of hypertrophic scarring remains high. These hypertrophic scars often lead to functional impairment and psychological morbidity, and may incur more healthcare expenses.
It has been observed that fetal wounds heal in a near perfect fashion without the formation of scars. The difference between fetal and adult cutaneous wound healing process has attracted much interest in the characterization of factors implicated in the scar formation process. Among various factors identified through this approach, transforming growth factor-beta (TGF-β) is believed to play a key role in the process of both wound healing and scar formation.
TGF-β is a type of cytokine that regulates cell growth, differentiation, apoptosis, fibrogenesis, and development in a wide range of biological systems. Typically, TGF-β is secreted in a latent form which is later activated through proteolytic activations mediated by TGF-β receptor type I (TGFBRI) and type II (TGFBRII). Human TGF-β has three isoforms, TGF-β1, TGF-β2 and TGF-β3; these isoforms have overlapping functions and predominantly mediate their effects through the intracellular SMAD pathway. In the cutaneous wound healing process, TGF-β1 is reported as being associated with immunosuppression, fibroblast migration and proliferation, wound contraction, granulation tissue formation, collagen synthesis and deposition, angiogenesis and re-epithelialization. Investigating the differential expressions of TGF-β isoforms in fetal and adult wounds found that the levels of TGF-β1 and TGF-β3 are respectively elevated in adult and fetal wounds, suggesting that TGF-β1 may be responsible for the scar formation in adult wounds whilst the scarless wound healing in fetal wounds may be due to increased level of TGF-β3.
Researchers have attempted to down-regulate the level of TGF-β1 at the wound site, using anti-TGF-β1 antibody or siRNA targeting TGF-β1, in hopes of achieving scarless wound healing. However, the TGF-β/SMAD signaling pathway involves dozens of mediators, and wound healing is a multi-stage process that requires different mediators in different stages. Accordingly, simply reducing the level of TGF-β1 does not yield satisfactory results. For example, full-thickness wounds in TGF-β1-deficient mice heal normally in the early stage; however, the TGF-β1 deficiency leads to inflammation that interferes with later stages of wound healing in these mice. Further, in TGF-β1 knockout mice lacking T and B cells (Tgfb1−/− Scid−/− mice), wound healing is delayed by approximately 1 week, as compared with immuno-deficient (Scid−/−) mice that have the wild-type Tgfb1 allele (Crowe M et al., J. Invest. Dermatol, 2000, 115, 3-11).
In view of the foregoing, there exists a need in the art for providing an effective treatment for reducing scar formation.